Abstract:

The invention relates to a solid pharmaceutical composition comprising
donepezil hydrochloride hydrate and a process for its preparation. In
particular it relates to a composition and a process wherein the
donepezil hydrochloride retains its polymorphic form and is therefore
highly stable against conversion into other polymorphic forms.

Claims:

1. Solid pharmaceutical composition comprising donepezil hydrochloride in
the form of a hydrate and excipients, and having a water content of 3 to
10% by weight (determined by Karl Fischer).

2. Composition according to claim 1 having a water content of 4 to 7% by
weight (determined by Karl Fischer).

8. Composition according claim 1, wherein the excipients include at least
one disintegrant selected from starch, crospovidone, and low-substituted
hydroxypropyl cellulose.

9. Composition according to claim 1 comprising as excipient:(A) 1 to 50%
by weight of donepezil hydrochloride,(B) 1 to 90% by weight of
diluent,(C) 1 to 90% by weight of binder,(D) 1 to 40% by weight of
disintegrant, and optionally(E) 0.1 to 10% by weight of lubricant.

10. Composition according to claim 1, wherein the water content of the
donepezil hydrochloride hydrate and the various excipients used in the
composition is adjusted in such a way that a migration of water from the
excipients to the donepezil hydrochloride or vice versa is prevented.

11. Composition according to claim 10 comprising:(a) donepezil
hydrochloride, and(b) excipents, which are present in the composition in
the amount of more than 11%, preferably more than 15%, more preferably
more than 20% based on the total composition weight, and(c) excipients,
which are present in the composition in the amount of less than 11%,
preferably less than 15%, more preferably less than 20% based on the
total composition weight,wherein the water content of excipients (b), in
% by weight, minus the water content of active ingredient (a), in % by
weight, is less than 4.0% (by weight), preferably less than 3.0% (by
weight), most preferably less than 2.0% (by weight) (determined by Karl
Fischer).

12. Composition according to claim 1, which is in the form of a tablet.

13. Process for the preparation of a solid pharmaceutical composition
according to comprising donepezil hydrochloride in the form of a hydrate
and excipients, and having a water content of 3 to 10% by weight
(determined by Karl Fischer) said process comprising the step of mixing
and processing donepezil hydrochloride and excipients to the desired
composition.

14. Process according to claim 13 comprising:(i) granulating a mixture of
excipients using water as granulation liquid to give a granulate,(ii)
adding donepezil hydrochloride and excipients to the granulate to give a
compression mixture,(iii) compressing the compression mixture to the
desired form, and(iv) optionally applying a coating.

15. Process according to claim 13 comprising:(i) granulating a mixture of
donepezil hydrochloride and excipients using water as granulation liquid
to give a granulate,(ii) adding excipients to the granulate to give a
compression mixture,(iii) compressing the compression mixture to the
desired form, and(iv) optionally applying a coating.

16. Process according to claim 14, wherein the temperature of the mixture
and of the granulate does not exceed 50.degree. C. during the granulating
step.

17. Process according to claim 14, wherein the water content of the
granulate is 0.5 to 2.5%, preferably 1.0 to 2.0% determined as loss on
drying at 85.degree. C., 20 minutes.

18. Process according to claim 14, wherein the water content of the
compression mixture is 1.0 to 6.0%, preferably 1.5 to 5.0% determined as
loss on drying at 85.degree. C., 20 minutes.

[0002]The invention relates to a solid pharmaceutical composition
comprising donepezil hydrochloride and a process for its preparation. In
particular it relates to a composition and a process wherein the
donepezil hydrochloride retains its polymorphic form and is therefore
highly stable against conversion of polymorphic forms.

[0004]WO 97/46527 describes a method for the preparation of the
polymorphic forms I to V and of the amorphous form of do-nepezil
hydrochloride. The polymorphs are characterised by characteristic peaks
in the powder X-ray diffraction pattern and wave numbers (cm-1) of
infrared absorption spectra in potassium bromide. Different methods for
producing the form I of donepezil hydrochloride are described. However,
no specific solid pharmaceutical compositions are disclosed, let alone
data on the stability of donepezil hydrochloride, either in the amorphous
or in the different crystal forms, when incorporated in such a
composition.

[0005]EP-A-1 086 706 discloses compositions of donepezil which have been
stabilised against the effect of light and heat by the addition of an
organic acid. It is also shown by examples that the use of organic acids
results, after storing the composition at elevated temperatures, in the
production of less impurities in comparison to the use of hydrochloric
acid.

[0006]EP-A-1 378 238 describes pharmaceutical compositions which comprise
donepezil hydrochloride in amorphous form. It is further discussed in
this document that it is not an easy task to reproducibly prepare
compositions including the desired polymorphic form of donepezil
hydrochloride since it is showing polymorphism and since similar
procedures may nevertheless lead to different crystalline forms.

[0007]Thus, the prior art does not deal with the problem of avoiding a
conversion of the polymorphic form of donepezil hydrochloride when
processing it to the desired solid composition. Further, the prior art
also does not address the problem of stabilising the polymorphic form of
donepezil hydrochloride during the shelf-life of a corresponding solid
composition.

[0008]These problems are surprisingly solved by the present invention.

[0009]The solid pharmaceutical composition according to the invention
comprises donepezil hydrochloride and excipients, and has a water content
of 3 to 10%, preferably 4 to 7% and more preferably 5 to 6% by weight as
determined by Karl Fischer (test performed according to Ph. Eur. 2.5.12,
e.g. on a Karl Fischer titrator Metrohm 7012 KF Titrino). The donepezil
hydrochloride is used in form of a hydrate, preferably in the form of the
monohydrate.

[0010]It has unexpectedly been found out that it is critical to control
the water content of the composition to lie in the above range in order
to avoid the undesired conversion of the specific polymorphic form of
donepezil hydrochloride in the composition to other hydrated or anhydrous
polymorphic forms. In particular the conversion of hydrated forms into
anhydrous forms is a problem with conventional compositions.

[0011]The donepezil hydrochloride is present in the compositions of the
invention in crystalline form. More preferably the donepezil
hydrochloride is present in one of various polymorphic forms, in
particular as polymorph I or IV. These polymorphic forms of donepezil
hydrochloride as well as the preparation thereof are disclosed in WO
97/46527 the contents of which is incorporated herein by reference. The
compositions of the present invention thus preferably contain polymorph I
and/or polymorph IV of donepezil hydrochloride in the form of a hydrate.

[0012]A composition is particularly preferred wherein the donepezil
hydrochloride is donepezil hydrochloride of polymorphic form I and in
particular the monohydrate of polymorphic form I. Such a composition has
been found to be very stable against undesired changes to other
polymorphic form(s) of the active ingredient.

[0013]In a further preferred embodiment the composition according to the
invention is such that the average particle size of the donepezil
hydrochloride is 5 to 300 μm, preferably 10 to 150 μm. The average
particle size is determined by laser method on 10 Malvern Mastersizer.

[0014]Donepezil hydrochloride hydrate of form I or form IV is preferably
prepared by suspending donepezil hydrochloride in a solvent.
Alternatively donepezil hydrochloride can be prepared from donepezil base
and hydrochloric acid. Preferably a mixture of methanol and water is used
as the solvent. Optionally other alcohols, such as ethanol or
isopropanol, or mixtures of alcohols with water can be used. The
formation of donepezil hydrochloride hydrate form I or form IV depends
upon the water content in the solvent mixture. The suspension is heated
until the donepezil hydrochloride has completely dissolved in the
solvent. Optionally this solution can be filtered trough 1 μm
filtration cartridge. The solution of donepezil hydrochloride is then
cooled to approximately 40° C. Donepezil hydrochloride hydrate of
form I or form IV is precipitated from this solution by the addition of
isopropyl ether, isopropyl acetate, ethyl acetate, butyl acetate,
isobutyl methyl ketone, tert.-butyl methyl ether or heptane.

[0015]It is further preferred that the particle sizes of the other
excipients used in the pharmaceutical compositions of the present
invention are within the range of D90<500 μm, preferably D90<350
μm, in order to ensure homogeneity of the compression mixture and
homogeneous granulation and compression. D90 means that at least 90% by
volume or weight of the particles have a particle size below the
specified value.

[0016]The excipients present in the composition according to the invention
can be diluents such as microcrystalline cellulose, powdered cellulose,
lactose (anhydrous or preferably monohydrate), compressible sugar,
fructose, dextrates, other sugars such as mannitol, sorbitol, lactitol,
sacharose or a mixture thereof, siliconised microcrystalline cellulose,
calcium hydrogen phosphate, calcium carbonate, calcium lactate or
mixtures of diluents. Preferably, the excipients include at least one
diluent, selected from microcrystalline cellulose and lactose
monohydrate.

[0017]The composition according to the invention can also comprise
binders, such as polyvinyl pyrrolidone, microcrystalline cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted
hydroxypropyl cellulose, hydroxypropylmethyl cellulose or other cellulose
ethers, starch, pregelatinised starch, or polymethacrylate or mixtures of
binders. It is preferred that the excipients include at least one binder
selected from hydroxypropyl cellulose, starch, in particular corn starch,
pregelatinised starch and hydroxypropylmethyl cellulose. Low-substituted
hydroxypropyl cellulose is hydroxypropyl cellulose comprising from 5 to
16% by weight of hydroxypropoxy groups. Suitable low-substituted
hydroxypropyl celluloses are commercially available from Shin-Etsu
Chemical Co., Ltd. under the trade names LH-11, LH-20, LH-21, LH-22,
LH-30, LH-31 and LH-32.

[0018]Further, disintegrants can also be present, such as starch, e.g.
pregelatinised starch, corn starch or others, sodium starch glycolate,
crospovidone, microcrystalline cellulose, carboxymethylcellulose sodium,
polacrilin potassium, low-substituted hydroxypropyl cellulose or mixtures
thereof. If used as a disintegrant, microcrystalline cellulose is
preferably used in an amount of 5 to 15% by weight. It is preferred that
the excipients include at least one disintegrant selected form starch,
crospovidone and low-substituted hydroxypropyl cellulose.

[0019]The disintegrants can be added to the other excipients according to
the process used in the state of the art, either in the process of
granulating and/or in the preparation of the compression mixture.

[0020]Further, lubricants can also be present as excipients, such as
stearic acid, magnesium stearate, calcium stearate, sodium
laurylsulphate, hydrogenated vegetable oil, hydrogenated castor oil,
sodium stearyl fumarate, talc, or macrogols or mixtures thereof. It is
preferred that the excipients include at least one lubricant selected
from hydrogenated castor oil, talc and magnesium stearate.

[0021]A composition is particularly preferred which comprises: [0022](A)
1 to 50%, preferably 1 to 40%, more preferably 1 to 30% by weight of
donepezil hydrochloride, [0023](B) 1 to 90%, preferably 20-85% by weight
of diluent, [0024](C) 1 to 90%, preferably 10-40% by weight of binder,
[0025](D) 1 to 40%, preferably 10-40% by weight of disintegrant, and
optionally [0026](E) 0.1 to 10%, preferably 0.1-5% by weight of
lubricant.

[0027]Even more preferred are compositions comprising the above defined
preferred excipients. If not indicated otherwise all percentages given
herein are by weight based on the total weight of the composition.

[0028]Investigations have also shown that the achieving of a stable
composition in terms of avoiding conversion of the polymorphic form of
donepezil hydrochloride used is surprisingly possible by a rather small
difference of the water contents of the donepezil hydrochloride and the
excipients. Thus the water content of the active ingredient and the
various excipients used in the compositions of the present invention is
adjusted in such a way that a migration of water from the excipients to
the donepezil hydrochloride or vice versa is prevented.

[0029]In a preferred embodiment the invention relates to a solid
pharmaceutical composition comprising: [0030](a) donepezil
hydrochloride, and [0031](b) excipients, which are present in the
composition in the amount of more than 11% (e.g. more than 11 to 99%),
preferably more than 15% (e.g. more than 15 to 99%), more preferably more
than 20% (e.g. more than 20 to 99%) based on the total composition
weight, and [0032](c) excipients, which are present in the composition in
the amount of less than 11% (e.g. 0.1 to less than 11%), preferably less
than 15% (e.g. 0.1 to less than 15%), more preferably less than 20% (e.g.
0.1 to less than 20%) based on the total composition weight,wherein the
water content of excipients (b), in % by weight, minus the water content
of active ingredient (a), in % by weight, is less than 4.0% (by weight),
preferably less than 3.0% by weight, most preferably less than 2.0% by
weight, determined by Karl Fisher (test performed according to Ph. Eur.
2.5.12, e.g. on a Karl Fischer titrator Metrohm 7012 KF Titrino).
Excipient (c) may be absent even though it is preferred that excipient
(c) is present.

[0035]The donepezil hydrochloride (a) is preferably a donepezil
hydrochloride hydrate, more preferably a hydrate of polymorphic form IV
and in particular of form I.

[0036]It is assumed that the small difference in terms of water content of
the ingredients of this composition effectively prevents a migration of
water from the donepezil hydrochloride to the excipients and vice versa,
thereby stabilising donepezil hydrochloride in the form originally used,
i.e. preventing a conversion e.g. of donepezil hydrochloride polymorphic
form I into another polymorphic form.

[0037]The composition according to the invention is preferably in form of
a coated or uncoated tablet, e.g. fast disintegrating tablet or orally
disintegrating tablet, a capsule or in the form of pellets. The
composition can also take the form of a powder mixture, of a granulate or
of mini tablets filled in capsules. An immediate release composition is
preferable.

[0038]The composition according to the invention can be prepared by a
process which comprises mixing and processing donepezil hydrochloride and
excipients to the desired composition.

[0039]As the composition is characterised by a specific water content as
given above, its components, in particular their amount and their water
content, and the way of processing them to the composition are selected
such that the desired water content is achieved in the composition. This
can in particular be effected by wetting a part of or all excipients with
water, which can be achieved in a separate step or as part of the
production process, for example in the course of a granulation step with
water or aqueous granulation liquids.

[0040]Due to the problem that in particular donepezil hydrochloride in
monohydrate form, e.g. donepezil hydrochloride of form I, can transform
into an anhydrous form, the choice of the process and of the excipients
is critical to achieve the desired water content of the composition or
the desired small difference as to water content of donepezil
hydrochloride and excipients which result in a highly stable final
product.

[0041]A wetting of excipients can be performed in conventional granulation
equipment by spraying of purified water into the excipients by
conventional techniques. Wetting can also be effected by direct addition
of purified water onto a mixture of excipients during a mixing operation
in a proper mixing device, e.g. high-shear mixer.

[0043]In case the composition is defined by the difference as to the water
contents of donepezil hydrochloride and excipients, then their respective
water content is to be adjusted accordingly in the process for its
preparation.

[0044]The process for preparing the composition according to the invention
can be carried out as a granulation process or a direct compression
process.

[0045]In a preferred embodiment, the granulation process comprises
[0046](i) granulating a mixture of excipients using water as granulation
liquid to give a granulate, [0047](ii) adding donepezil hydrochloride and
excipients to the granulate to give a compression mixture, [0048](iii)
compressing the compression mixture to the desired form, and [0049](iv)
optionally applying a coating.

[0050]Thus, in this embodiment, a granulate is prepared in step (i) which
does not include the active ingredient donepezil hydrochloride.

[0051]In another preferred embodiment, the granulation process comprises
[0052](i') granulating a mixture of donepezil hydrochloride and
excipients using water as granulation liquid to give a granulate,
[0053](ii') adding excipients to the granulate to give a compression
mixture, [0054](iii') compressing the compression mixture to the desired
form, and [0055](iv') optionally applying a coating.

[0056]Thus, in this embodiment a granulate is prepared in step (i') which
includes active ingredient.

[0057]The excipients used in steps (ii) and (ii'), respectively, can be
the same or different excipients as used in steps (i) and (i'),
respectively.

[0058]It has been found preferable that the temperature of the granulate
in a granulation process does not exceed 50° C. during the
granulating step. It is assumed that this is useful to prevent undesired
changes of the polymorph used to other forms as may occur when using high
temperatures, in particular to remove granulation liquid after a
granulating process.

[0059]In particular the temperature used when drying the wet granulate
should be low, e.g. the temperature of the inlet air in a fluid bed dryer
should be around 70° C. or lower, to ensure that the temperature
of the granulate does not exceed 50° C. Use of high temperatures
accelerates transformation of a hydrated form to other hydrated or
anhydrous forms.

[0060]Further, it has also been found beneficial to adjust the water
content of the granulate to 0.5 to 2.5%, preferably 1.0 to 2.0% by weight
(determined as loss on drying, at 85° C., 20 minutes, e.g. with a
Mettler Toledo HR73 halogen moisture analyser).

[0061]It is also preferred that the water content of the compression
mixture is 1.0 to 6.0%, preferably 1.5 to 5.0% by weight (determined as
loss on drying, at 85° C., 20 minutes, e.g. with a Mettler Toledo
HR73 halogen moisture analyser).

[0062]For drying the granulation conventional drying devices such as a
fluid-bed dryer or drying chambers can be used.

[0067]Also in the direct compression process, it is preferred that the
water content of the compression mixture is 1.0 to 6.0%, preferably 1.5
to 5.0% by weight, (determined as loss on drying, at 85° C., 20
minutes, e.g. with a Mettler Toledo HR73 halogen moisture analyser).

[0068]In the above processes according to the invention the compression,
in particular to tablets, can be effected using rotary press machines
from different manufacturers.

[0069]Optionally, the tablets can be coated with conventional materials
used for film coating, i.e. as described in Pharmaceutical Coating
Technology, 1995, edited by Graham Cole. The film coating formulations
preferably contain the following components: polymer(s), plasticizer(s),
colourant(s)/opacifier(s), vehicle(s). In the film coating suspension
minor quantities of flavours, surfactants and waxes can be used. The
majority of the polymers used in film coating are preferably either
cellulose derivatives, such as cellulose ethers, or acrylic polymers and
copolymers. High molecular weight polyethylene glycols, polyvinyl
pyrrolidone, polyvinyl alcohol and waxy materials can also be used.

[0070]Typical cellulose ethers are hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose.
Suitable acrylic polymers include synthetic polymers with diverse
functionalities. They may be further modified to enhance swelling and
permeability by the incorporation of materials such as water soluble
cellulose ethers and starches in order to ensure complete
disintegration/dissolution of the film.

[0079]Conventional equipment can be used for applying a coating, such as a
Wurster coating system or conventional coating pans.

[0080]It has been found to be beneficial that, the water content of film
coated tablets is 3 to 10% by weight, preferably 4 to 7% by weight and
more preferably 5 to 6% by weight (determined by the Karl-Fischer method,
test performed according to Ph. Eur. 2.5.12, e.g. on a titrator Metrohm
7012 KF Titrino).

[0081]It was surprisingly found out that the processes according to the
invention effect virtually no undesired conversion of the donepezil
hydrochloride used as starting material to other forms. This was in
particular shown when using donepezil hydrochloride hydrate, which did
not undergo appreciable conversion into other hydrated forms or into
other anhydrous forms.

[0082]Further, also the final composition showed a surprisingly high
stability against undesired conversions of the donepezil hydrochloride,
in particular of donepezil hydrochloride hydrate, upon storage.

[0083]Although accelerated conditions (50° C.) were used for
stability testing and tablets were not packaged in contact packing
material, e.g. blisters, donepezil hydrochloride hydrate remained
unchanged. The stability of composition according to the invention was
proven by characteristic peaks in the powder X-ray diffraction pattern.
The result of this test is shown in FIG. 1. FIG. 1 shows an X-ray
diffraction pattern of tablets comprising donepezil hydrochloride hydrate
(upper curve) as well as of pure donepezil hydrochloride hydrate (lower
curve). The absence of other diffraction peaks in the tablets pattern
indicates the absence of other forms of donepezil hydrochloride.

[0084]The present invention will now be further illustrated with reference
to Examples and a Figure.

[0086]111.8 g of donepezil hydrochloride hydrate, 1587 g of lactose
monohydrate, 857 g of pregelatinised starch and 429 g of corn starch were
homogenised in a biconic mixer for 10 minutes at 26 rpm. Finally, 16 g of
magnesium stearate were added and the mixing was continued for 3 minutes.
The obtained compression mixture was compressed on an automatic rotary
press machine, fitted with round punches to give tablet cores, the weight
of 10 cores was 300 mg. Subsequently, the cores were coated with the
coating suspension, which contains hydroxypropylmethyl cellulose (70% by
weight), polyethylene glycol (5% by weight), titanium dioxide (20% by
weight), talc (4% by weight) and iron oxide (1% by weight) until the
average weight of 10 film coated tablets was 308 mg.

[0087]The water content of donepezil hydrochloride hydrate was 5.0%
determined by Karl Fischer method, test performed according to Ph. Eur.
2.5.12, on a titrator Metrohm 7012 KF Titrino.

[0088]The amount of water in the obtained tablets was 6.0% by weight,
determined by the Karl-Fischer method which was performed according to
Ph. Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

EXAMPLE 2

Tablets by Granulation Process

[0089]5030 g of microcrystalline cellulose, 1920 g of lactose monohydrate,
840 g of corn starch and 250 g of hydroxypropylcellulose were homogenised
in a high-shear mixer. The homogenised mixture was sprayed with purified
water and granulated in a high-shear mixer/granulator. The wetted mixture
was dried in a fluid-bed dryer using an inlet air temperature of
70° C. The obtained dry granulate was sieved using a sieving
machine. Subsequently, 313 g of donepezil hydrochloride hydrate were
mixed with the granulate in a biconic mixer. Finally, 45 g of magnesium
stearate were admixed to obtain a compression mixture.

[0090]The compression mixture was compressed to obtain tablets. Some of
these tablets were provided with a film coating as described in Example
1.

[0091]The amount of water in the obtained tablets was 5.4% by weight,
determined by the Karl-Fischer method which was performed according to
Ph. Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

EXAMPLE 3

Tablets by Granulation Process

[0092]5030 g of lactose monohydrate, 1920 g of microcrystalline cellulose
and 250 g of hydroxypropylcellulose were homogenised in a high-shear
mixer. The homogenised mixture was sprayed with purified water and
granulated in a high-shear mixer/granulator. The wetted mixture was dried
in a fluid-bed dryer using an inlet air temperature of 70° C. The
obtained dry granulate was sieved using a sieving machine. Subsequently,
313 g of donepezil hydrochloride hydrate and 840 g of low-substituted
hydroxypropylcellulose were mixed with the granulate in a biconic mixer.
Finally, 45 g of magnesium stearate were admixed to obtain a compression
mixture.

[0093]The compression mixture was compressed to obtain tablets. Some of
these tablets were provided with a film coating as described in Example
1.

[0094]The amount of water in the obtained tablets was 5.1% by weight,
determined by the Karl-Fischer method which was performed according to
Ph. Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

EXAMPLE 4

Tablets by Granulation Process

(a) Preparation Process

[0095]3540 g of lactose monohydrate, 1430 g of microcrystalline cellulose,
600 g of corn starch and 180 g of hydroxypropyl cellulose were
homogenised in a high-shear mixer. The homogenised mixture was sprayed
with purified water and granulated in a high-shear mixer/granulator. The
wetted mixture was dried in a fluid-bed dryer using an inlet air
temperature of 70° C. The obtained dry granulate was sieved using
a sieving machine. The granulate showed the following particle size
distribution:

[0096]The water content for dry granulate determined by Karl-Fischer
method was 4.8%. The water determination was performed according to Ph.
Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

[0097]Subsequently, 223 g of donepezil hydrochloride hydrate were mixed
with the granulate in a biconic mixer. Finally, 32 g of magnesium
stearate were admixed to obtain a compression mixture.

[0098]The compression mixture was compressed into tablets. The average
weight of 10 tablets was 200 mg. A portion of the tablets was provided
with a coating as described in Example 1.

[0099]The amount of water in the obtained tablets was determined to be
5.5% by the Karl Fischer method which was performed according to Ph. Eur.
2.5.12, on a titrator Metrohm 7012 KF Titrino.

(b) Stability Test of Tablets

[0100]Accelerated conditions were used for stability testing. Tablets
containing donepezil hydrochloride hydrate were stored for 30 days at a
temperature of 50° C. Tablets were not packaged in a contact
packing material such as blisters. The stability of the composition
according to the invention was proven by characteristic peaks in the
powder X-ray diffraction pattern. The result of this test is shown in
FIG. 1.

[0101]FIG. 1 shows an X-ray diffraction pattern of tablets comprising
donepezil hydrochloride hydrate. Tablets were prepared by water
granulation (upper curve) and stored 30 days at 50° C./dry (middle
curve). Donepezil hydrochloride hydrate is shown in the bottom curve. The
absence of other diffraction peaks in the tablets pattern stored 30 days
at 50° C./dry indicate that there are no other (anhydro and hydro)
forms of donepezil hydrochloride present. Donepezil hydrochloride hydrate
in the composition according to the invention remains unchanged.

EXAMPLE 5

Tablets by Granulation Process

[0102]Example 4 was repeated with the exception that the 180 g of
hydroxypropyl cellulose were replaced by 180 g of hydroxypropylmethyl
cellulose.

[0103]The amount of water in the obtained tablets was 5.3% by weight,
determined by the Karl-Fischer method which was performed according to
Ph. Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

EXAMPLE 6

Tablets by Granulation Process

[0104]279 g of donepezil hydrochloride hydrate, 4491 g of macrocrystalline
cellulose, 1714 g of lactose monohydrate, 223 g of hydroxypropylcellulose
and 750 g of low-substituted hydroxypropylcellulose were homogenised in a
high shear mixer. The homogenised mixture was sprayed with purified water
and granulated in a high-shear mixer/granulator. The wetted mixture was
dried in a fluid-bed dryer using an inlet air temperature of 70°
C.

[0105]The obtained dry granulate was sieved using a sieving machine.
Finally, 40 g of magnesium stearate were admixed to obtain a compression
mixture.

[0106]The compression mixture was compressed into tablets. The average
weight of the tablets was 250 mg/tablet. Some of these tablets were
provided with a coating as described in Example 1.

[0107]The amount of water in the obtained tablets was 5.8% by weight,
determined by the Karl-Fischer method which was performed according to
Ph. Eur. 2.5.12, on a titrator Metrohm 7012 KF Titrino.

EXAMPLE 7

Tablets by Granulation Process

[0108]Example 6 was repeated with the exception that the 4491 g of
microcrystalline cellulose and 1714 g of lactose monohydrate were
replaced by 4491 g of lactose monohydrate and 1714 g of microcrystalline
cellulose. The drying time in the fluid-bed dryer was 19 minutes. The
result of particle size distribution for tabletting mixture was as
follows:

[0109]The amount of water in the tablets was 5.7% (determined by the
Karl-Fischer method performed according to Ph. Eur. 2.5.12, on a titrator
Metrohm 7012 KF Titrino).

EXAMPLE 8

Preparation of Donepezil Hydrochloride Form I

[0110]50.6 g donepezil base were suspended in methanol (300 ml) at room
temperature and heated to 60° C. to get a clear solution. 11 ml
conc. hydrochloric acid were added at 25 to 30° C. with measuring
pH (3.2±0.2). The solution of donepezil hydrochloride warmed to
40-45° C.; it was slowly added to cooled (0-5° C.)
diisopropyl ether (600 ml) maintaining the temperature at 5-10° C.
The suspension was stirred for another half an hour. The product was
filtered and dried in vacuum (30-50 mbar) at a temperature of
30-35° C. The drying was controlled by measuring the water content
(Karl Fischer not more than 4.5%). The yield was 52.66 g (91%).

EXAMPLE 9

Crystallisation of Donepezil Hydrochloride Form I

[0111]50 g donepezil hydrochloride were suspended in methanol (300 ml) and
8 ml of water, heated to 60-65° C. to get a clear solution. Then
this hot solution was slowly added to cooled (0-5° C.) diisopropyl
ether (600 ml) maintaining the temperature at 5-10° C. The
suspension was stirred for another half an hour. The product was filtered
and dried in vacuum (30-50 mbar) at a temperature of 30-35° C. The
drying was controlled by measuring the water content as described in
Example 8. The yield was 47.39 g (91%).

EXAMPLE 10

Preparation of Donepezil Hydrochloride Polymorph I

[0112]5 g donepezil hydrochloride were suspended in methanol (30 ml) and
0.8 ml of water, heated to 60-65° C. to get a clear solution. Then
this hot solution was slowly added to cooled (0-5° C.) isopropyl
acetate (60 ml) maintaining the temperature at 5-10° C. The
suspension was stirred for another half an hour to one hour. The product
was filtered and dried in vacuum (30-50 mbar) at a temperature of
30-35° C. The drying was controlled by measuring the water content
as described in Example 8 and the loss on drying. The yield was from 1.8
to 4.9 g.

EXAMPLE 11

Crystallization of Donepezil Hydrochloride Form IV

[0113]1 g donepezil hydrochloride was suspended in isopropanol (6 ml) and
1 ml of water, heated to reflux to get a clear solution. Then this hot
solution was slowly added to cooled (0-5° C.) diisopropyl ether
(12 ml) maintaining the temperature at 5-10° C. The suspension was
stirred for another half an hour to one hour. The product was filtered
and dried in vacuum (30-50 mbar) at a temperature of 30-35° C. The
drying was controlled by measuring the water content as described in
Example 8 and the loss on drying to get 0.98 g donepezil hydrochloride of
form IV.

EXAMPLE 12

Preparation of Donepezil Hydrochloride Polymorph I

[0114]4.98 kg of donepezil base were suspended at room temperature
(20-25° C.) in methanol (30 l) and heated to 60-65° C. to
get a clear solution. The solution was cooled to 30° C., filtered
through a 1 μm filtration cartridge and cooled to 20-25° C.
1.05 l of conc. hydrochloric acid were added at 25-30° C. with
measuring the pH (3.2±0.2). The solution of donepezil hydrochloride
was warmed to 40-45° C. and slowly added to cooled (0-5°
C.) diisopropyl ether (60 l) maintaining the temperature at 5-10°
C. The suspension was stirred for another half an hour at 5-10° C.
Then, the product was filtered off to obtain 8.45 kg of a wet substance.
The wet donepezil hydrochloride hydrate (57%) was dried in vacuum (30-50
mbar) using the following procedure: Firstly, the product was dried at
25° C. under a slight stream of nitrogen. When it became possible
the product was granulated through a sieve of 3×3 mm and through a
sieve of 1.2×1.2 mm (in process control, loss on drying LOD 24.3%).
The temperature of drying was raised to 30-35° C. when the LOD was
5.1%. The drying was also controlled by measuring the assay of water. One
hour later the assay of water was 2.77% and LOD was 3.60%. The drying was
stopped and the substance was exposed to humid air (relative humidity
under 60%) to achieve an assay of water of 4.34% (Karl Fischer). The
yield of the dried product was 4.9 kg.

EXAMPLE 13

Crystallization of Donepezil Hydrochloride Polymorph I

[0115]10.2 kg of donepezil hydrochloride were suspended in 62 l of
methanol and 1.6 l of water and heated to 60-65° C. to get a clear
solution. The solution was cooled to 50° C., filtered through a 1
μm filtration cartridge and cooled to 40-45° C. Then this hot
solution was slowly added to cooled (0-5° C.) diisopropyl ether
(122 l) maintaining the temperature at 5-10° C. The suspension was
stirred for another half an hour at 5-10° C. The product was
filtered to obtain 15.9 kg of wet substance. The wet donepezil
hydrochloride hydrate (58%) was dried in vacuum (30-50) mbar using the
following procedure: Firstly, the product was dried 1 h at 25° C.
under a slight stream of nitrogen. Then the product was granulated
through a sieve of 3×3 mm (in process control, loss on drying (LOD)
21.4%). The drying was continued sieving through a sieve of 1.2×1.2
mm every hour. The temperature of drying was raised to 30-35° C.
when LOD was 5.8%. The drying was also controlled by measuring the assay
of water. After two hours drying at 30° C. the assay of water was
3.66% and LOD was 3.75%. The drying was stopped and the substance was
exposed to humid air (relative humidity under 60%) to achieve an assay of
water of 4.14% (Karl Fischer). The yield of the dried product was 9.2 kg.

[0116]Alternatively, vacuum filter dryer, rotary vacuum dryer or air dryer
can be used for drying donepezil hydrochloride hydrate.

[0117]Furthermore, wet donepezil hydrochloride hydrate having an assay of
50-70% can also be dried under vacuum or via an air fluide bed dryer
using one or more of the following steps: [0118]drying of donepezil
hydrochloride hydrate to have donepezil hydrochloride hydrate comprising
30-50% by weight of solvents, [0119]drying with stirring or granulating
every qualified period (e.g. every hour), [0120]drying at 20-25°
C. until loss on drying (LOD) is below 6%, [0121]drying at 20-25°
C. under a slight stream of nitrogen, [0122]drying at 20-25° C.
under vacuum below 50 mbar, [0123]drying at 30-35° C. until loss
on drying (LOD) is below 4.8%, [0124]exposing to humid air (relative
humidity under 60%) when the assay of water is below 4.1% to achieve an
assay of water not more than 5.0% (Karl Fischer).